JPS6345279A - Novel pyrido(2,3-d)pyrimidine derivative, production thereof and pharmaceutical composition containing said compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 and R2 are lower alkyl; R3 and R4 are H, OH, halogen, nitro, amino, lower alkylamino, hydroxy-lower alkylamino, lower alkenylamino, hydroxyamino, hydrazino or azido) and its salt. EXAMPLE:5-Amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione. USE:A medicine having low toxicity, useful as a remedy and preventive for various allergic diseases such as bronchial asthma, uriticaria, etc., and especially effective against chronic diseases. It is expected also as a cardiotonic or bronchodilator, etc. PREPARATION:The compound of formula I wherein R<3> and R<4> are H can be produced by reacting the compound of formula II (X is H or CH3) with phosphorus oxyhalide, thionyl halide or triphenylphosphine dihalide in dimethyl sulfoxide solvent and reducing the reaction product.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a novel pyridoC2,3-d]pyrimidine derivative and a pharmaceutically acceptable salt thereof, a method for producing the same, and a compound containing the compound as an active ingredient. PHARMACEUTICAL COMPOSITIONS.

(Prior Art) It is known that the production of in-vivo chemical substances called chemical mediators, such as histamine, serotonin, and 5R3-A, plays an important role in the expression of various allergic symptoms in the human body. Therefore, drugs that antagonize these substances and/or suppress the release of these substances are useful for treating or preventing allergic diseases, and several compounds have been developed for this purpose to date. has been used.

(Problems to be Solved by the Invention) While researching drugs that effectively act against allergic diseases, the present inventors discovered that the pyrido (2,3-d
) The present invention was completed based on the discovery that pyrimidine derivatives have excellent antiallergic effects.

The purpose of the present invention is to provide novel pyrido(2,3-d)pyrimidine derivatives having antiallergic activity and pharmaceutically acceptable salts thereof, methods for producing the same, and treatment and prevention of various allergic diseases containing the compounds as active ingredients. The aim is to provide agents for

(Means for Solving the Problems) The compound of the present invention is a novel pyrido(2,3-d)pyrimidine derivative represented by the following general formula (1).

(In the formula, R1 and R are the same or different lower alkyl groups, R1 and R4 are the same or different, hydrogen, hydroxyl group, halogen, nitro group, 7mino group, lower alkyl 7mino group, hydroxy lower represents an alkylamino group, lower alkenylamino group, hydroxyamino group, hydrazino group or azido group) More specifically, in the above general formula (+), R1 and R
1 is the same or different linear or branched lower alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-
Represents butyl, tert-butyl, pentyl group, etc.

R1 and R4 are the same or different and each may have hydrogen, a hydroxyl group, a halogen such as fluorine, chlorine, bromine, or iodine, preferably methylamino, dimethylamino, or ethylamino, which may have chlorine, a nitro group, an amino group, or a hydroxyl group. , diethylamino, pro-ruamino, isopro-ruamino, butylamino, isobutylamino, sec-butylamino, Ler
Straight or branched lower alkylamino groups having 1 to 5 carbon atoms such as t-butylamino and pentylamino groups, vinyl,
It represents a linear or branched lower alkenylamino group having 1 to 5 carbon atoms, such as propenyl, isopropenyl, allyl, butenyl, pentynyl group, hydroxyamino group, hydrazino group, or azido group.

Among the compounds of the present invention, particularly preferred compounds are as follows.

・1,3-dimethylpyrido(2,3-d)pyrimidine-
2,4-dione 5-hydroxy-1,3-dimethylpyrido (2,3-
d] Pyrimidine-2,4-dione/5-chloro-1,3-dimethylpyrido (2,3-d)
Pyrimidine-2,4-dione/5-chloro-1,3-diethylpyrido (2,3d) Pyrimidine-2,4-dione/5-chloro-1-isobutyl-3-methylpyrido (2
, 3-d) Pyrimidine-2,4-dione 6-nitro 1,3-dimethylpyrido (2,3-d) Pyrimidine-2
,4-dione 5-amino-1,3-dimethylpyrido (2,3-d)
Pyrimidine-2,4-dione/5-amino-1,3-diethylpyrido (2,3-d)
Pyrimidine-2,4-dione 5-amino-1-isobutyl-3-methylpyrido (2
, 3-d) Pyrimidine-2,4-dione/6-amino-
1,3-dimethylpyrido(2,3-d)pyrimidine-2
,4-dione/7-amino-1,3-dimethylpyrido (2,3-d)
Pyrimidine-2,4-dione 7-amino-1-isobutyl-3-methylpyrido (2
, 3d) Pyrimidine-2,4-dione 7-amino-5
-Hydroxy-1,3-dimethylpyrido (2,3-d)
Pyrimidine-2,4-dione/5-methylamino-13
-dimethylpyrido[2,3-d)pyrimidine-2,4-
Dione 5-methylamino-1,3-diethylpyrido C2,3
-d) Pyrimidine-2,4-dione/5-ethylamino-1,3-dimethylpyrido [2,3
-d) Pyrimidine-2,4-dione/5-propylamino-1,3-dimethylpyrid [2,
3-d) Pyrimidine-2,4-dione/5-isopropylamino-1,3-dimethylpyrido (
2,3-d) Pyrimidine-2,4-dione/5-isopropylamino-1,3-diethylpyride (2,3-d)
Pyrimidine-2,4-dione/5-butylamino-1,
3-dimethylpyrido[2,3-d)pyrimidine-2,4
-dione 5- tert-butylamino-1,3-dimethylpyrido(2,3-d)pyrimidine-2,4-dione 5-
tert-butylamino-1,3-diethylpyride (2
,3-d) Pyrimidine-2,4-dione/5-7lylamino-1,3-dimethylpyrido [2,3-d]pyrimidine-2,4-dione/5-hydroxyamino-1,3-dimethylpyrido (2
,3-d) Pyrimidine-2,4-dione 5-(2-hydroxyethyl)amino-1,3-dimethylpyrido(2
,3-d) Pyrimidine-2,4-dione/5-hydrazino-1,3-dimethylpyrido (2,3-d)pyrimidine-2,4-dione/5-azido-1,3-dimethylpyrido (2,3-d) -d)
Pyrimidine-2,4-dione The pyrido(2,3-d)pyrimidine derivatives of the present invention include pharmaceutically acceptable salts of the compound represented by the general formula (1), such as sodium, potassium, etc. alkali metals, alkaline earth metals such as calcium and magnesium, other metal salts such as aluminum, or inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, citric acid, and lactic acid. Examples include acid addition salts with acids and salts with organic bases such as ammonia.

These salts can be converted into free pyrido (4) of the present invention by a known method.
, 3-d) can be produced from pyrimidine derivatives, or can be converted into each other.

When optical isomers exist in the compound of the present invention,
The present invention includes any of the di-integrated, d-integrated, and β-integrated.

Next, a method for producing the compound of the present invention will be described.

General formula (■): (wherein R1 and R2 have the same meanings as in the above general formula (1), X represents hydrogen, a methyl group or a cyanomethyl group, and Y represents an amino group or a dimethylamino methylene amino group, ) The compound of the present invention represented by the general formula (1) can be produced by the following method using the uracil derivative represented by the formula (1) as a starting material.

tl) General formula (n
') and dimethylformamide (DMF
) and phosphorus oxyhalides such as phosphorus oxychloride, thionyl halides such as thionyl chloride, or triphenylphosphine dihalogens such as triphenylphosphine dichloride and triphenylphosphine cyfuromide by appropriately heating and reacting for several hours. Compounds of the present invention having halogens such as fluorine, chlorine, bromine, and iodine in positions can be obtained.

Furthermore, the above 5-halogen compound and ammonia, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, butylamine, isobutylamine, 5ec-butylamino, tert-butylamine, pentylamine, which may have a hydroxyl group. Linear or branched lower alkylamines having 1 to 5 carbon atoms such as groups, vinylamines, propenylamines, isopropenylamines, orylamines, butenylamines, pentynylamines, etc. By reacting with 1 to 5 lower alkenylamine, hydroxyamine, hydrazine or sodium azide, a substitution reaction with 5-position halogen is performed, and methylamine, dimethyl which may have an amino group or hydroxyl group at 5-position amino, ethylamino,
Linear or branched lower alkylamino groups having 1 to 5 carbon atoms such as diethylamino, propylamine, isopropylamino, butylamino, isobutylamino, 5ec-butylamino, tert-butylamino, pentylamino groups, vinylamino, Straight-chain or branched lower alkenylamino groups having 1 to 5 carbon atoms, such as propenylamino, isopropenylamino, allylamino, butenylamino, and pentynylamino groups, hydroxyamino groups, hydrazino groups, or azido groups can be introduced. .

This reaction can be carried out in an alcohol such as methanol or ethanol, or in a suitable solvent such as DMF, at room temperature or with appropriate heating or reflux for several hours. However, when using a substance with a low boiling point such as ammonia, it is also necessary to seal the reaction system.

The 5-halogeno compound or 5-azide compound obtained as described above can be obtained by a conventional one-component method, such as catalytic reduction using palladium-carbon, etc., according to the present invention, in which the 5-position is hydrogen or an amino group, respectively. It can be a compound.

Alternatively, a compound represented by the general formula (n) where X is a methyl group and Y is an amino group and dimethylformamide dimethylacecool, dimethylformamide diethyl acecool, or dimethylformamide diptylacecool are mixed in an appropriate solvent such as DMF. The compound of the present invention having a hydroxyl group at the 5-position can be obtained by reacting for several hours with appropriate heating.

This 5-hydroxy body is converted into the above-mentioned phosphorus oxyhalide,
By treatment with a halogenating agent such as thionyl halide or triphenylphosphine dihalogen, 5
The 5-halogen compound can also be produced by performing a substitution reaction between the hydroxyl group at the position and the halogen.

(2) Obtaining the compound of the present invention having an amino group at the 7-position by reacting a compound represented by the general formula (■') in which X is hydrogen and Y is an amino group with cyanomethylenetriphenylphosphorane. Can be done. This manufacturing method is based on Wi
This is an application of the ttig reaction, and the reaction can be carried out by heating and refluxing for several hours in dry acetonitrile under a stream of inert gas such as argon.

(3) By reacting a compound represented by the general formula (■') in which X is hydrogen and Y is a dimethylamino methylene amino group with nitromethane for several hours with appropriate heating in the presence of a base such as triethylamine, The compound of the present invention having a nitro group at the 6-position can be obtained, and further reduced to the 6-amino compound by a conventional reduction method, such as catalytic reduction using palladium-carbon, etc. .

(4) A compound represented by the general formula (n) in which X is a cyanomethyl group and Y is an amino group is reacted with a base such as sodium carbonate by appropriately heating or refluxing for several hours to close the ring, and the 5-position A compound of the present invention having a hydroxyl group at the 7-position and an amino group at the 7-position can be obtained.

The obtained compound of the present invention can be obtained by distillation, chromatography,
It was purified by conventional means such as recrystallization, and identified by elemental analysis, melting point measurement, IR, NMRSUV, mass spectrometry, etc.

The invention will be explained in further detail by the following examples.

(Example) Example 1゜1l) 5.92g of 5-acetyl-6-amino-1,3
-Dimethyluracil and 7.34 g of phosphorus oxychloride were added to 100% DMF and heated at 60°C for 2 hours. i
After leaking out solvent 8 under reduced pressure, water was added and the precipitated crude crystals were collected by filtration and recrystallized from ethyl acetate to give 5.34 g of 5-chloro-1,3-dimethylpyrido(2,3-d)pyrimidine-
2,4-dione (compound 1) was obtained.

Yield near 9% Melting point: 175-177 °C Elemental analysis: C*HsCIN, 0% as Ox
8% N% Calculated value: 47.91 3.57 18.62
Actual value: 48.07 3.56 18.52
NMR(DMSO-dh)δ-3,38(311,
s), 3.55(3)1. s).

7.40 (IH, d, J-5Hz), 8.55 (l)
I, d, J-5Hz) Similarly, 5-chloro-1,3-
Diethylpyrido(2,3-d)pyrimidine-2,4-dione and 5-chloro-1-4so-butyl-3-methylpyrido[2,3-d)pyrimidine-2,4-dione were obtained.

(210.34 g of Compound 1 was dissolved in 100 methanol, palladium-carbon was added, and catalytic reduction was performed. Decolorizing charcoal was added to the reaction solution, which was heated and then filtered. The filtrate was leaked under reduced pressure.

Ethanol was added, the crude crystals were collected by filtration, and recrystallized from ethanol to give 0.24 g of 1,3-dimethylpyrid (2,3-
d] Pyrimidine-2,4-dione (compound 2) was obtained.

Yield: 84% Melting point: 160-161°C Elemental analysis: 0% as C, H, N30□ 8%
N% Calculated value: 56.54 4.75 21.98
Actual value: 56.53 4.78 21.98
N M RCDMSOJ&) δ-3,30(38,
s), 3.55 (3H, s).

7.32(1)1. dd, J=5Hz, 7.5Hz),
8.35 (IH, dd.

J=2.5Hz, 7.5Hz), 8.68(LH, d
d, J-2,5Hz, 5Hz) Example 2゜(Dl, 35g of compound 1 was dissolved in DMFIO-, 9
0.52 g of 0% sodium azide was added, and the mixture was stirred at room temperature for 6 hours. After leaking the solvent under reduced pressure, water was added and the precipitated crystals were collected by filtration to give 1.16 g of 5-azido-1,3-dimethylpyrido(2,3-d)pyrimidine-2,4-dione (
Compound 3) was obtained.

Yield: 83% Melting point: 102-108°C (decomposition) IR (
KBr): Similarly to W--x-2110 (N3), 5-azido-1,3-diethylpyride (2,3-dl
Pyrimidine-2,4-dione and 5-azido-1-1s
o-Butyl-3-dimethylpyrido[2,3-d)pyrimidine-2,4-dione was obtained.

(2) 1.33 g of Compound 3 was dissolved in 400 g of methanol, and 300 a+g of palladium-carbon was added thereto for contact dissolution.

Decolorizing charcoal was added to the reaction solution, heated, and then filtered. After leaking the filtrate under reduced pressure, ethanol was added and the precipitated crude crystals were collected by filtration and recrystallized from ethanol to give 0.87 g of 5-amino-1,3
-dimethylpyrido(2,3-d)pyrimidine-2,4-
Dione (compound 4) was obtained.

Yield near 4% Melting point: 233-235°C Elemental analysis: 0 as Cq H+ o Na Oz
% 8% N% Calculated value: 52.42 4.89 27.17
Actual value: 52.66 4.87 26.89
NMR(DMSO-dh) δ-3,20(3)
1. s), 3.40(3)1. sL6.40 (ltl
, d, J=6Hz), 7.90(LH, d, J=6H
z), 7.90 (2H, br) The following compound was obtained in the same manner.

5-amino-1,3-diethylpyrido(2,3-d)pyrimidine-2,4-dione Compound 5)
Rate: 64.8% Melting point: 216-217 °C Elemental analysis: C+ IH+ a N -0 as 0
% 8% N% Calculated value: 56.40 6.02 23.92
Actual value: 56.54 5.99 23.86
NMR(CDCl3) δ-3,20(3)1
．． t, J=6Hz), 1.30(3)1°t, J=
61(z), 4.12(21,q, J=7Hz), 4
．． 38 (2t1.q.

J=7)1z), 6.31 (1M, d, J=6Hz)
, 7.90 (LH, br).

8.08 (IH, d, J=6tlz) 5-amino-5-iso-butyl-1-methylpyrido (
2,3-d) Pyrimidine-2,4-dione (compound 6) Yield: 67% Melting point: 183-185°C Elemental analysis: Clz H+ h Na Oz・4/
25 0% as H, O 8% N% Calculated value: 57.39 6.55 22.31
Actual value: 57.76 6.47 22.04
NMR(DMSO-DA) δ-0,8T(6)
1. d, J-6Hz), 2.0-2.5 (IH, m)
, 3.29(311,s), 4.08(2B,d,
J-611z).

6.51 (ILd, J=6tlz), 7.90 (1)
! , br), LH4(1)1°d, J・6Hz) Example 3°+110.4 g of compound 1 and 1.86 g of methylamine (30% methanol solution) were added to DMF 10-, and the mixture was heated at room temperature. Stirred for 2 hours. ? After the solvent 8 was leaked under reduced pressure, the water was strained and the precipitated crude crystals were collected by filtration and recrystallized from ethyl acetate to give 0.23 g of 5-methylamino-1,3-dimethylpyrido C2,3-d)pyrimidine- 2,4-dione (compound 7) was obtained.

Yield: 63% Melting point: L79-180°C Elemental analysis: C+oH+□NaOz 0%
HoAN oA Calculated value: 54.54 5.49 25.44
Actual value: 54.40 5.48 25.21
NMR(DMSO-dh) δ-0,8T(3H
, d, J=511z), 3.19(3)1. s),
3.40(3)1. s), 6.35 (111, d, J
-611z).

8.05 (IH, d, J=6Hz), 8.90 (LH
,br) Similarly, 5-methylamino-1,3-diethylpyrido(2,3-d)pyrimidine-2,4-dione(
Compound 8) was obtained.

Yield: 52% Melting point: 114℃ Elemental analysis: C+zH+mNa0z'215Hz 0% 8% N% Calculated value: 56.41 6.63 21.93
Actual value: 56.15 6.42 21.90
N~I R(CDCl2) δ-1,25(3H,t
, J=7Hz), 1.29 (3H.

t, J=711z), 4.10(2H,q, J=6
11z), 4.38 (2H, QIJ=6Hz),
6.29 (LH, d, J=611z), 8.15
(IH, d.

J=61(z), 9.22(1)1. br) (2)
The following compound was obtained in the same manner as ill using allylamine and isopropylamine instead of methylamine.

5-allylamino-1,3-dimethylpyrido (2,3-
d) Pyrimidine-2,4-dione (Compound 9) Yield near 2% Melting point: 120-121 °C Elemental analysis: C9A as Clz H1-N, Ot
8% N% Calculated value: 58.52 5.73 22.75
Actual measurement value: 58.28 5.78 22.6O
NMR(CDCh) δ-3,30(31Ls)
, 3.64 (3H, s).

3.93 (2H, s), 4.25 (2H, m),
5.80 (111, s), 6.30 (18, d,
J-711z), 8.10(1)1. d, J=711
z), 9.38 (IH.

br) 5-isopropyl-1,3-dimethylpyrido [2,3-
dl Pyrimidine-2,4-dione (Compound 10) Yield: 77.9% Melting point: 127-128°C Elemental analysis: 0% as C1□Hlb Na Oz
11% N% Calculated value: 58.05 6.50 22.57
Actual value: 58.13 6.68 22.58
N M R(D?l5O-D,)δ-1,23(6Ld
, J・6Hz), 3.23(3H,s), 3.46
(311,s), 3.82(ILn), 6.49(
III, d.

J=611z), 8.05 (IH, d, J-6Hz)
, 9.07 (111, d, J = 8 Hz) (3) Using hydroxyamine hydrochloride instead of methylamine, fi
5-hydroxyamino-1,3-dimethylpyrido(2,3-d)pyrimidine-2,4-dione (
Compound 11) was obtained.

Yield: 84% Melting point: 11B -120°C Elemental analysis: C18. 0% as N a Os
8% N% Calculated value: 48.65 4.54 25.21
Actual value: 48.85 4.45 25.34
NMR(CDCl2.D?l5O-Di) δ
-3,30(3H,s), 3.62(3H,s),
6.85 (IH, d, J=6Hz), 8.15 (11
(,d.

J=6Hz), 9.29(IH,s), 10.55
(IH, br) (4) 5-hydrazino-1,3-dimethylpyrido(2,3-d)pyrimidine-2,4-dione (compound ″#Jl 2) was obtained.

Yield: 90% Melting point: 191-192°C Elemental analysis: 0% as C9H+ + N s Oz
8% N% Calculated value: 48.86 5.01 31.66
Actual value: 49.12 5.05 31.6
ON M R (1)? l5O-+1h) δ-1,2
5 (3H, s), 3.48 (3Il, s).

4.72(2)1. brs), 6.94 (IH, d,
J-6Hz), 8.12(1)1°d, J=611z
), 9.84 (IH, brs) (5) 5-(2-hydroxyethyl)amino-1,3 in the same manner as +11, using ethanolamine hydrochloride instead of methylamine.
-dimethylpyrido(2,3-d)pyrimidine-2,4-
Dione (compound 13) was obtained.

Yield: 68.8% Melting point: 163°C IR (KBr): 3300.1685.1645.
1590.1570 cm-'NMR(DMSO-
Di) δ-1,25(38,s), 3.48(3
H,s).

3.62 (2H, ddd, J-6Hz), 4.95 (
2)1. t, J=5tlz).

6.48 (IH, d, J-6Hz), 8.05 (IH
, d, J-6tlz), 9.26 (LH, t, J-
5Hz) Example 4 5-acetyl-6-amino-13-dimethyluracil 0
．． 8 g was dissolved in DMF, dimethylformamide diptylacetal 4- was added, and the mixture was reacted at 80°C for 8 hours.

? 8 medium was forcefully leaked out, and after separation using a silica gel column, 0.59 g of 5-hydroxy-1 was recrystallized from ethanol.
,3-dimethylpyrido(2,3-d)pyrimidine-2,
4-dione (compound 14) was obtained.

Yield: 70.2% Melting point: 162-163 °C Elemental analysis: 0% as CwHwNiOs 8%
N% Calculated value 7 52.17 4.38 20.28 Actual value: 52.31 4.29 20.32N
MR(DMSO-dJ δ-3,30(311,
s), 3.55 (3H, s).

6.78 (III, d, J=611z), 8.42 (
IH, d, J = 6tlz).

12.30 (IH, br) Example 5 0.18 g of 6-amino-5-formyl-1,3-dimethyluracil and 0.45 g of cyanomethylenetriphenylphosphorane were added to a desiccant setonitrile 20- The mixture was heated under reflux for 12 hours under an argon atmosphere. After cooling, the precipitated crystals were collected by filtration to obtain 0.08 g of 7-amino-L3-dimethylpyrido(2,3-d)pyridine-2,4-dione (Compound 15).

Yield: 39% Melting point: 290-295°C (sublimation) Elemental analysis: C9H+. 0% H% as Na Oz
N% Calculated value: 52.42 4.89 27.14
Actual value: 52,50 4.97 27.02
NMR(CF3COO)I) δ-3,57(3
11,s), 3.84 (3H,s).

6.93 (III, d), 8.52 (01, d) Example 6゜fl) 0.24 g of 5-formyl-6-dimethylaminomethyleneamino-1,3-dimethyluracil and 0.5 triethylamine - to nitromethane 10. t plus 80
Heated at ℃ for 2.5 hours. ? After the solvent 8 was leaked under reduced pressure, ether was added to the residue, the precipitated crude crystals were collected by filtration, and recrystallized from ethanol to give 0.14 g of 6-nitro-13-dimethylpyrido(2,3-d)pyrimidine-2, 4-dione (
Compound 16) was obtained.

Yield: 58.8% Melting point: 203-205°C Elemental analysis: 0% H% as CqH*Na0a
N% Calculated value: 45.76 3.41 23.72
Actual value: 45.82 3.43 23.85
NMR(DMSO-d,) δ-3,63(3H
,s), 3.81(3H,s).

8.61 (III, d, J-3Hz), 9.43 (18
, d, J=3 Hz)+210.08 g of Compound 14 was dissolved in methanol, and 100 μm of palladium-carbon was added to carry out catalytic reduction. Decolorizing charcoal was added and the mixture was heated and filtered. The solvent was leaked under reduced pressure and recrystallized from methanol to give 0.05 g of 6
-Amino-1,3-dimethylpyrido(2,3-d)pyrimidine-2,4-dione (Compound 17) was obtained.

Yield: 71.6% Melting point: 219-220°C NMR (DMSO-di) δ-3,30(3)
1. s), 3.50(3)1. s).

5.50 (211,s), 7.60CIH,d, JJ
Hz), 8.17 (IH, d.

J-311z) Example 7 1.21 g of 6-amino-3-(2-cyanoacetyl)-1,3-dimethyluracil and 2.90 g of sodium carbonate were added to water 20- and heated under reflux for 1 hour. I let it happen. The precipitate precipitated on cooling was collected by filtration to give 1.09 g of 7-amino-
5-hydroxy-1,3-dimethylpyrido (2,3-d
) Pyrimidine-2,4-dione (compound 18) was obtained.

Yield: 91% Melting point: >300°C Elemental analysis: CqH+. N40. as 0%
H% N% Calculated value: 48.65 4.54 25.22
Actual value: 48.37 4.48 25.09
N M R((:F3COOH) δ−3,52(3
8,s), 3.8031(,s).

6.20(IH,s) Example 8゜(11) 5-tert-
Butylamino-1,3-dimethylpyrido (2,3-d)
Pyrimidine-2,4-dione (compound 19) was obtained.

Melting point: 154°C (2) By the same method as in Example 5, 7-amino-1
-isobutyl-3-methylpyrido(2,3-d)pyrimidine-2,4-dione (compound 20) was obtained.

Melting point: 152-154° C. (Action) The pyrido(2,3-d)pyrimidine derivative of the present invention is a compound having excellent antiallergic action.

The pharmacological actions of the compounds of the present invention will be described below.

+11 Acute Toxicity Using a group of 5 male ICR mice, the acute toxicity of the compound of the present invention was investigated using the Liftfield-Wilcoxon method based on the mortality rate 14 days after oral administration of the test drug.

An example of the results is shown in Table 1.

Table 1 Test drugs LDs. (mg/kg) Compound 4
850 Compound 5 >1000 Compound 7 1050 Compound 9 >1000 Compound 10 850 Compound 11 >1000 Compound 15 >1200 Theophylline 417 (2) Antiallergic effect The antiallergic effect of the compounds of the present invention was measured by rough) PCA reaction.

A group of 6 male Wistar rats with separate dorsals (
Passive sensitization was performed by administering an anti-DNP-Asc solution diluted with physiological saline to four intradermal sites in the skin of a 6-year-old (age 6a). One hour after oral administration of the test drug, DNP-Asc?
A PCA reaction was induced by intravenously administering a mixture of equivalent amounts of 2% Evans filler solution (5 ml/l) and 2% Evans filler solution.

After 30 minutes, exsanguinate the top of the head to kill the layer, cut out the blue layer,
The amount of leaked dye was measured. In other words, 2N potassium hydroxide water? Dissolve the skin with 8 liquid, 2 N IJ acid aqueous solution,
After adding acetone and centrifugation, the resulting supernatant was
The amount of dye was measured by absorbance at o+, and the inhibition rate of dye leakage was determined.

An example of the results is shown in Table 2.

Table 2 Control - O Compound 2 20 51.2 Compound 4 20 68.7 Compound 5
20 79.2 Compound 7
20 73.7 Compound 8 20
76.4 Compound 9 20
67.9 Compound 10 20
86.6 Compound 11 20 74.
0 Compound 14 20 49.9 Compound 15 20 68.7 Compound 17
20 56.2 Theophylline
20 57.9 (Efficacy) As is clear from the above pharmacological experiment results, the pyrido[2,3-d)pyrimidine derivative of the present invention exhibits an antiallergic effect equivalent to or superior to that of theophylline, and has low toxicity. Therefore, it is useful when used as a medicine. That is, the compounds of the present invention can be administered orally, and are useful as therapeutic and preventive agents for various allergic diseases and diseases, such as bronchial asthma, measles, allergic rhinitis, allergic conjunctivitis, and allergic skin diseases.
This is particularly advantageous when adapting to chronic diseases.

In addition, as an indicator of antiallergic activity other than the PCA reaction, we investigated the phosphogesterase inhibitory effect and found that the compound of the present invention inhibited phosphogesterase activity with a very low fQK. Since the compound of the present invention has a sterase inhibitory effect, it can be expected to be used not only as a therapeutic agent for allergic diseases but also as a cardiotonic agent, a bronchodilator, and the like.

The compound of the present invention can be combined with a suitable pharmaceutical carrier or diluent to form a medicament, and can be formulated by any conventional method to form a solid, semisolid, liquid or gaseous form for oral or parenteral administration. It can be formulated into the following dosage forms.

For formulation, the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts (the compounds of the present invention may be used alone or in appropriate combinations, or may be used in combination with other pharmaceutically active ingredients). For example, it may be combined with a bronchodilator, an antihistamine, a tranquilizer, or a tranquilizer.

As an oral preparation, it can be used as it is or with appropriate additives,
ff4 Along with conventional excipients such as Eva lactose, mannitol, corn starch, and potato starch, binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, and gelatin, corn starch, potato starch, sodium carboxymethyl cellulose, etc. disintegrants, talc, lubricants such as magnesium stearate, other fillers, wetting agents, buffers,
It can be made into tablets, powders, granules or capsules by appropriately combining preservatives, fragrances and the like.

Furthermore, the compound of the present invention can be mixed with various bases, such as an oil base such as cacao butter, an emulsion base, a water-soluble base such as macrogol, a hydrophilic base, etc. to produce suppositories. be able to.

The injection may be a liquid or a suspension in an aqueous or non-aqueous solvent, such as distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, etc. .

For use as an inhaler or aerosol, the compounds of the invention may be present in the form of a solution, suspension or finely divided powder, together with a gaseous or liquid propellant and, if desired, the usual excipients such as wetting agents or dispersing agents. The compound of the present invention to be filled into an aerosol container together with the above compound may be in a non-pressurized dosage form such as a nebulizer or an atomizer.

Furthermore, depending on the type of disease, it can be formulated into dosage forms other than those mentioned above, such as eye drops, ointments, poultices, etc., which are most suitable for the treatment.

The desired dosage of the compound of the present invention varies depending on the subject to be administered, the dosage form, the method of administration, the administration period, etc., but in order to obtain the desired effect, the compound of the present invention is generally administered at a dose of 1 to 1,000 mg per day for adults. The compound of the present invention can be administered orally in an amount of preferably 1 to 500 g, and one to several units of a unit preparation containing an appropriate amount of the compound of the present invention can be administered per day.

In the case of parenteral administration (eg, injection), the daily dose is preferably at a dose level of 3 to 10 times the above-mentioned dose.

Examples of formulations of pharmaceutical compositions containing the compound of the present invention as an active ingredient are shown below, but the present invention is not limited thereto.

Prescription example 1. (Tablet) Ingredients per tablet (+g) Compound of the present invention 100 lactose
130 Corn Starch 40 Magnesium Stearate
10 prescription examples 2. (Capsule) Ingredients Per capsule (tag) Compound of the present invention 50 lactose
250 prescription examples 3. (Injection) Ingredients per ampoule (mg) Compound of the present invention i.

Sodium chloride Appropriate amount 11ml total Prescription example 4゜ (Suppositories) Ingredients per unit (-g) Compound of the present invention 20 Prescription examples 5. (Inhalation agent) Ingredients per unit (g) Compound of the present invention 1 lactose
5 total 6g (fill into an inhaler designed to inhale 50+mg of powder per dose)

Claims (3)

[Claims] (1) General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are the same or different lower alkyl groups, R_3 and R_4 are the same or different and hydrogen, hydroxyl group, halogen, nitro group, amino group, lower alkylamino group, hydroxy lower alkylamino group, lower alkenylamino group, hydroxyamino group,
Represents a hydrazino group or an azide group. ) A novel pyrido[2,3-d]pyrimidine derivative and a pharmaceutically acceptable salt thereof. (2) General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, R_1 and R_2 are the same or different lower alkyl groups, and X' represents hydrogen or a methyl group.) The compound represented by is reacted with dimethylformamide and phosphorus oxyhalide, thionyl halide, or triphenylphosphine dihalogen, and then reduced, or
or by reaction with ammonia, lower alkylamine, lower alkenylamine, hydroxy lower alkylamine, hydroxyamine or hydrazine, or by reaction with sodium azide and subsequent reduction, or by reaction with general formula (I
General formula ( I ′) characterized by reacting a compound represented by
): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I') (In the formula, R_1 and R_2 are each the same or different lower alkyl group, R'_3 and R'_4 are the same or different and each are hydrogen or amino group. , lower alkylamino group,
Represents a hydroxy lower alkylamino group, lower alkenylamino group, hydroxyamino group or hydrazino group. ) A method for producing a novel pyrido[2,3-d]pyrimidine derivative. (3) General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are the same or different lower alkyl groups, R_3 and R_4 are the same or different and hydrogen, hydroxyl group, halogen, nitro group, amino group, lower alkylamino group, hydroxy lower alkylamino group, lower alkenylamino group, hydroxyamino group,
Represents a hydrazino group or an azide group. ) A treatment and prophylactic agent for various allergic diseases containing at least one of the novel pyrido[2,3-d]pyrimidine derivatives represented by: and its pharmaceutically acceptable salts as an active ingredient.